Mitochondria are dynamic organelles altering their inner and outer membranes through fission and fusion mechanisms. In a response to shear stress, the mitochondria in endothelial cells (ECs) continuously undergo fusion and fission mechanisms.

We hypothesized that alteration in mitochondria dynamic could alter EC functions leading to vascular damage.

We investigated the role of Opa1 deficiency in ECs and vascular homeostasis using mice lacking the fusion protein Opa1 (heterozygous Opa1±mice).

Endothelium-mediated dilatation was lower in Opa1±than in Opa1+/+mice, without change in vascular contractility in isolated arteries. Flow-mediated ECs alignment was reduced in Opa1± compared to Opa1+/+mice. We then investigated mitochondrial dynamics-related proteins expression level in ECs submitted to a disturbed shear stress (evidenced by eNOS down-regulation and endothelin-1 up-regulation) and observed a reduction in fusion protein Opa1 mRNA expression and an increase in fission protein Drp1 mRNA expression level. As shear stress determines atherogenesis in large arteries, we investigated mitochondrial dynamics-related proteins in various areas in the mouse aorta. In the area submitted to low shear stress, Opa1 mRNA expression was reduced and Drp1 mRNA expression was increased compared to other parts of the aorta submitted to higher shear stress. These observations led to investigate atherosclerosis in Opa1± mice. These mice, when crossed with LDLr-/- mice and fed high-fat diet, develop more atherosclerosis than Opa1+/+mice.

Thus, reduced mitochondrial fusion altered endothelium-dependent functions and exacerbated plaque formation in atherosclerotic mice. And, in order to investigate the mechanism by which the ECs respond to shear stress, we are studying the effect of mitochondrial dynamic proteins on endothelial cells alignment and functions.